Is AFM p.Phe505Leu (c.1515C>A) pathogenic?

AFM p.Phe505Leu (c.1515C>A) is classified Uncertain significance in AFM (ClinVar, Single submitter, 1 submitter; last evaluated 2025-12-03). AlphaMissense: likely pathogenic (0.8221); Very rare (popmax 8.47e-05%, nfe).

How common is AFM p.Phe505Leu (c.1515C>A) in the general population?

AFM p.Phe505Leu (c.1515C>A) is very rare (popmax 8.47e-05%, nfe) (gnomAD).

What do computational predictors say about AFM p.Phe505Leu (c.1515C>A)?

AlphaMissense predicts likely pathogenic (score 0.8221) — an in-silico prediction, not a clinical call.

AFM p.Phe505Leu

c.1515C>A · VCV4638765

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8221 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.47e-05%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.8221	likely pathogenic · top 4% in AFM
REVEL	0.313	indeterminate
SaProt	LLR -5.18	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.92	GERP 0.2, phastCons 1
Regional constraint	o/e 1.10	unconstrained · MANE · 21 kb · p 0.0081 · regional, not allelic
Overall
CADD	21.0	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.47e-05% European (non-Finnish) · 1/1,179,972 alleles

Overall 6.84e-05% 1/1,461,738 alleles · very rare

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: AFM
Protein: p.Phe505Leu
Coding: c.1515C>A
MANE Select: NM_001133
Type: single nucleotide variant
Location: chr4:73500096 (GRCh38)
Gene constraint: LOEUF 1.44 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 90.47 · 3 PDB
Residue 505: a disulfide bond; the albumin 3 domain; an α-helix

Full AFM gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

AFM p.Ala100Val Uncertain significance ★ ⚠ same type
AFM p.Ala150Pro Uncertain significance ★ ⚠ same type
AFM p.Ala241Val Uncertain significance ★ ⚠ same type
AFM p.Ala352Glu Uncertain significance ★ ⚠ same type
AFM p.Ala352Val Uncertain significance ★ ⚠ same type
AFM p.Ala397Thr Uncertain significance ★ ⚠ same type
AFM p.Ala397Val Uncertain significance ★ ⚠ same type
AFM p.Ala439Pro Uncertain significance ★ ⚠ same type

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/afm-p-phe505leu (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown